KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: Implication for Cerebral Cavernous Malformation disease

KRIT1 (CCM1) is a disease gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease of proven genetic origin affecting 0.3â0.5% of the population. Previously, we demonstrated that KRIT1 loss-of-function is associated with altered redox homeostasis and abnormal activation of the redox-sensitive transcription factor c-Jun, which collectively result in pro-oxidative, pro-inflammatory and pro-angiogenic effects, suggesting a novel pathogenic mechanism for CCM disease and raising the possibility that KRIT1 loss-of-function exerts pleiotropic effects on multiple redox-sensitive mechanisms. To address this possibility, we investigated major redox-sensitive pathways and enzymatic systems that play critical roles in fundamental cytoprotective mechanisms of adaptive responses to oxidative stress, including the master Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), a pivotal stress-responsive defense enzyme involved in cellular protection against glycative and oxidative stress through the metabolism of methylglyoxal (MG). This is a potent post-translational protein modifier that may either contribute to increased oxidative molecular damage and cellular susceptibility to apoptosis, or enhance the activity of major apoptosis-protective proteins, including heat shock proteins (Hsps), promoting cell survival. Experimental outcomes showed that KRIT1 loss-of-function induces a redox-sensitive sustained upregulation of Nrf2 and Glo1, and a drop in intracellular levels of MG-modified Hsp70 and Hsp27 proteins, leading to a chronic adaptive redox homeostasis that counteracts intrinsic oxidative stress but increases susceptibility to oxidative DNA damage and apoptosis, sensitizing cells to further oxidative challenges. While supporting and extending the pleiotropic functions of KRIT1, these findings shed new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell predisposition to oxidative damage, thus providing valuable new insights into CCM pathogenesis and novel options for the development of preventive and therapeutic strategies

Models for the investigation of the results of MHD mode active control in RFX-mod

Development and application of a linear-MHD model to study plasma modes and their coupling.Sviluppo e applicazione di un modello MHD lineare per lo studio dei modi di plasma ed il loro accoppiamento

Power Electronic Converters Enabling the Power Sharing Solution in LVDC Smart Grids for the new Energy Communities

Power electronic converters represent the core of LVDC smart microgrids. They realize the backbone of the power sharing among the end-users, from the renewable energy generation to the load clusters. A typical application of LVDC smart grids is a residential building, where multiple end-users can gather in an energy community. In this building, a renewable energy source provides the required power to the loads, according to power splitting algorithms. The power sharing among the end-users is made possible through a double stage control system: a general control enables the power allocation among the end-users, while the local control on each converter realizes the interconnection between the smart microgrid and the low voltage distribution grid. In this paper, all the power electronic converters enabling the power sharing solution in a LVDC smart microgrid for the new energy communities are described. The stability of the control system is also tested under several stressing scenarios

A global approach to the management of EMR (Electronic Medical Records) of patients with HIV/AIDS in Sub-Saharan Africa: the experience of DREAM Software

Abstract Background The DREAM Project operates within the framework of the national health systems of several sub-Saharan African countries and aims to introduce the essential components of an integrated strategy for the prevention and treatment of HIV/AIDS. The project is intended to serve as a model for a wide-ranging scale-up in the response to the epidemic. This paper aims to show DREAM's challenges and the solutions adopted. One of the solutions is the efficient management of the clinical data regarding the treatment of the patients and epidemiological analyses. Methods Specific software for the management of the patients' EMR has been created within the DREAM programme in order to deal with the challenges deriving from the context in which DREAM operates. Setting up a computer infrastructure in health centres, providing a power supply, as well as managing the data and the project resources efficiently and reliably, are some of the questions that have been analysed in this study. Results Over the years this software has proved that it is able to respond to the need for efficient management of the clinical data and organization of the health centres. Today it is used in 10 countries in sub-Saharan Africa by thousands of professionals and by now it has reached its fourth version. The medical files of over 73,000 assisted patients are managed by this software and the data collected with it have become essential for the epidemiological research that is carried out to improve the effectiveness of the therapy. Conclusion Sub-Saharan Africa is the region hardest hit by HIV and AIDS in the world. However, the resources and responses adopted so far, to confront the epidemic, have at times been rather minimalist. The DREAM project has faced the battle against the epidemic by equipping itself with qualitative standards comparable to Western ones. The experience of DREAM has revealed that it is indeed possible to guarantee levels of excellence in developing countries, also in the sphere of ICT (Information and Communication Technology), thus making the intervention even more effective and contributing to bridging the digital divide.</p